Glucose Metabolism and the Default Mode Network in Health and Disease. 5P01NS080675-03. The overarching hypothesis in this proposal is that brain glucose metabolism outside of oxidative phosphorylation (which we refer to as glycolysis) plays an important role in brain function in health and disease. A large fraction of this glycolysis occurs in a network of brain areas dubbed the brain's default mode network (DMN). The DMN is noteworthy because it is more active in the resting state, is central to the functional organization of the brain, has the highest rate of glycolysis of any group of brain areas and is uniquely vulnerable to Alzheimer's disease. Diabetes has emerged as a significant risk factor for Alzheimer's disease and we considered how glucose metabolism might increase the vulnerability of the DMN to Alzheimer's disease. We specifically hypothesize that chronic hyperglycemia and insulin resistance increase glycolysis and amyloid-beta release in brain areas that are heavily reliant on glycolysis leading to increased amyloid-beta deposition and accelerating the pathogenesis of AD. P.I.: Marc E. Raichle.